Project 2: Racial/ethnic differences, impact on tumor microenvironment and mortality

项目2：种族/民族差异、对肿瘤微环境和死亡率的影响

基本信息

批准号：
10044050
负责人：
ULRIKE PETERS
金额：
$ 32.4万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044050
关键词：
16S ribosomal RNA sequencing Address African American Age Alaska Native Animals Archives Bacteria Bacteroides fragilis Behavioral Biological Assay Cancer Control Cancer Etiology Colorectal Colorectal Cancer Colorectal Neoplasms Communities Consensus Data Development Diet Dietary Practices Disease Ensure Environmental Exposure Epithelial Epithelium Escherichia coli Ethnic Origin Ethnic group Etiology Fatty acid glycerol esters Fiber Fusobacterium nucleatum Future Gene Expression Genomics Goals Health Hispanics Human Immune Incidence Individual Inflammation Intervention Lesion Light Link Minority Groups Native-Born Natural History Normal tissue morphology Not Hispanic or Latino Oncogenes Outcome Pathway interactions Patients Pattern Persons Play Population Population Group Prevalence Race Reporting Resources Risk Factors Role Shoulder Specimen Structure Suggestion Time Tissues Tumor Biology Tumor Burden Tumor Tissue United States bacterial community base burden of illness cancer diagnosis cancer health disparity cancer initiation cancer subtypes cancer survival case control colon cancer patients colon tumorigenesis colorectal cancer progression colorectal cancer risk design digital ethnic difference ethnic diversity fruits and vegetables gut bacteria gut microbiome gut microbiota microbial community microbiome microbiome components microbiota molecular subtypes mortality outcome forecast polyketide synthase premalignant prognostic racial and ethnic racial and ethnic disparities racial difference sex transcriptome sequencing translational research program tumor tumor microbiome tumor microenvironment tumor progression

项目摘要

Project Summary/Abstract of Project 2 Colorectal cancer (CRC) incidence and mortality vary substantially by race/ethnicity in the United States (US). Alaska Natives have among the highest reported rates of CRC in the world; African Americans also shoulder an elevated burden from this disease compared to other groups within the US. In exploring factors that may contribute to these observed disparities, minimal consideration has been paid to the potential contribution of the microbiome. Although the presence of a gut microbial community is common across all human populations, the composition of that community varies greatly – by sex, diet, and race/ethnicity. The composition of the gut microbiome has plausible implications for a variety of pertinent health outcomes, including CRC. Increasing evidence indicates that specific gut bacteria, or imbalances in bacterial populations, could play a role in the natural history of CRC. For example, Fusobacterium nucleatum has been suggested to infiltrate the colorectal epithelium, promote CRC by increasing oncogene expression and inflammation, and contribute to poorer CRC survival. However, many questions remain as to the contributions of the microbiome to CRC across population groups, and the implications of those contributions. The objective of this study is to identify differences in the tumor-associated microbiome in CRC by race/ethnicity, associations of the tumor-associated microbiome with other aspects of the tumor microenvironment, and the impact on CRC survival. In Aim 1, we will assess differences in the bacterial community in CRC by race/ethnicity, focusing on both suspected candidate bacteria with plausible roles in CRC pathways (i.e., F. nucleatum, enterotoxigenic Bacteroides fragilis, and polyketide synthase-positive Escherichia coli – Aim 1a) and agnostic community-wide assays (Aim 1b). In Aim 2, we will examine how our evaluated candidate bacteria (2a) and agnostic patterns of bacterial community structure (2b) relate to prognostically-relevant gene-expression-based CRC subtypes and immune profiles in CRC tissue, considering possible differences by race/ethnicity. Lastly, in Aim 3, we will evaluate the relationship of suspected candidate bacteria (3a) and agnostic patterns of bacterial community structure (3b) with CRC survival, again considering possible differences in associations by race/ethnicity. In pursuit of these Aims, we will conduct targeted candidate (e.g., F. nucleatum-specific) and agnostic global assays (i.e., 16S rRNA gene sequencing) to characterize the bacterial community in CRC for 840 CRC cases from existing study resources with coverage of four racial/ethnic groups: Alaska Native people (n=210), African Americans (n=210), Hispanics (n=210), and non-Hispanic whites (n=210). Generating and contrasting information on the tumor- associated microbiome across racially/ethnically diverse groups, and relating all these data to CRC outcomes will provide an opportunity to advance our understanding of the microbiota’s role(s) in CRC health disparities. Information gained from this project will inform future strategies for targeted interventions and CRC control with the goal of reducing observed disparities in CRC incidence and mortality.

项目2的项目摘要/摘要2 结直肠癌（CRC）的发病率和死亡率因种族/种族而在美国（美国）差异很大。阿拉斯加的当地人是世界上CRC报道的最高率之一。非裔美国人也肩负与美国境内其他群体相比，这种疾病的燃烧升高。在探索可能的因素时为这些观察到的分布做出贡献，对可能的贡献付出了最少的考虑微生物组。尽管肠道微生物群落的存在在所有人口中都是常见的，但通过性，饮食和种族/种族/种族/种族，该社区品种的组成很棒。肠道的组成微生物组对包括CRC在内的各种相关健康结果具有合理的影响。增加证据表明，特定的肠道细菌或细菌种群中的失衡可能在 CRC的自然历史。例如，已建议核细菌核禽浸入大肠上皮，通过增加致癌基因表达和注射来促进CRC，并有助于较差的CRC 生存。但是，关于微生物组对CRC的贡献仍然存在许多问题群体以及这些贡献的含义。这项研究的目的是确定 CRC中与肿瘤相关的微生物组通过种族/种族，与肿瘤相关的微生物组的关联与肿瘤微环境的其他方面以及对CRC存活的影响。在AIM 1中，我们将评估种族/种族的CRC细菌社区的差异，重点是两个可疑的候选细菌在CRC途径中具有合理的作用（即F. nucleatum，肠毒素菌菌素Fragilis和Polyketide 合酶阳性大肠杆菌 - AIM 1A）和不可知论的社区范围的测定法（AIM 1B）。在AIM 2中，我们将检查我们评估的候选细菌（2A）和细菌群落结构的不可知模式（2B）与基于预测的基因表达相关的CRC亚型和CRC组织中的免疫特征有关考虑种族/种族可能存在的差异。最后，在AIM 3中，我们将评估可疑的候选细菌（3A）和细菌社区结构的不可知模式（3B）与CRC 生存，再次考虑种族/种族的关联可能差异。为了追求这些目标，我们将进行有针对性的候选者（例如F. nutleatum特异性）和不可知的全球测定（即16S rRNA基因测序）表征现有研究资源的840个CRC案例中CRC中细菌群落的表征覆盖四个种族/族裔群体：阿拉斯加土著人（n = 210），非裔美国人（n = 210），西班牙裔（n = 210）和非西班牙裔白人（n = 210）。产生和对比有关肿瘤的信息在大致/种族多样的群体中相关的微生物组，并将所有这些数据与CRC结果联系起来将提供一个机会，以促进我们对CRC健康分布中微生物群的作用的理解。从该项目中获得的信息将为有针对性的干预措施和CRC控制的未来策略提供信息减少CRC事件和死亡率中观察到的分布的目的。